The survival of multicellular organisms is dependent on the maintenance and functioning of a variety of different cell types. Many cell types proliferate in the course of development, resulting in growth of the organism. Once development is complete, a homeostasis in cell numbers is typically achieved. In some cell types, such as central nervous system neurons, this homeostasis is maintained by a complete cessation of cell proliferation, while in other cell types, such as blood cells, a balance is achieved between cell proliferation and "physiological" cell death.
Physiological cell death occurs primarily through a "cell suicide" program, termed apoptosis. It is now thought that the apoptosis program is evolutionarily conserved among virtually all multicellular organisms, as well as among all the cells in a particular organism. Further, it is believed that in many cases, apoptosis may be a "default" program that must be actively inhibited in healthy surviving cells.
The decision by a cell to submit to apoptosis may be influenced by a variety of regulatory stimuli and environmental factors (Thompson, 1995). Physiological activators of apoptosis include tumor necrosis factor (TNF), Fas ligand, transforming growth factor .beta., the neurotransmitters glutamate, dopamine, N-methyl-D-aspartate, withdrawal of growth factors, loss of matrix attachment, calcium and glucorticoids. Damage-related inducers of apoptosis include heat shock, viral infection, bacterial toxins, the oncogenes myc, rel and E1A, tumor suppressor p53, cytolytic T-cells, oxidants, free radicals and nutrient deprivation (antimetabolites). Therapy-associated apoptosis inducers include gamma radiation, UV radiation and a variety of chemotherapeutic drugs, including cisplatin, doxorubicin, bleomycin, cytosine arabinoside, nitrogen mustard, methotrexate and vincristine. Toxin-related inducers of apoptosis include ethanol and .beta.-amyloid peptide.
Apoptosis can have particularly devastating consequences when it occurs pathologically in cells that do not normally regenerate, such as neurons. Because such cells are not replaced when they die, their loss can lead to debilitating and sometimes fatal dysfunction of the affected organ. Such dysfunction is evidenced in a number of neurodegenerative disorders that have been associated with increased apoptosis, including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, retinitis pigmentosa and cerebellar degeneration. Further, it is believed that apoptosis is associated ischemic injury, such as typically occurs in cases of myocardial infarction, reperfusion injury and stroke.
The present invention provides compositions and methods useful for diagnosis and therapeutic treatment of apoptosis, as well as for the isolation of novel compounds effective to alter apoptosis.